Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder
Pharmacological targeting of the dopamine D4 receptor (D4R)expressed in brain regions that control cognition, attention, and decision-makingcould be useful for several neuropsychiatric disorders including substance use disorders (SUDs). This study focused on the synthesis and evaluation of a novel...
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| Veröffentlicht in: | Journal of medicinal chemistry 2023-09, Vol.66 (17), p.12141-12162 |
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| creator | Boateng, Comfort A. Nilson, Ashley N. Placide, Rebekah Pham, Mimi L. Jakobs, Franziska M. Boldizsar, Noelia McIntosh, Scot Stallings, Leia S. Korankyi, Ivana V. Kelshikar, Shreya Shah, Nisha Panasis, Diandra Muccilli, Abigail Ladik, Maria Maslonka, Brianna McBride, Connor Sanchez, Moises Ximello Akca, Ebrar Alkhatib, Mohammad Saez, Julianna Nguyen, Catherine Kurtyan, Emily DePierro, Jacquelyn Crowthers, Raymond Brunt, Dylan Bonifazi, Alessandro Newman, Amy Hauck Rais, Rana Slusher, Barbara S. Free, R. Benjamin Sibley, David R. Stewart, Kent D. Wu, Chun Hemby, Scott E. Keck, Thomas M. |
| description | Pharmacological targeting of the dopamine D4 receptor (D4R)expressed in brain regions that control cognition, attention, and decision-makingcould be useful for several neuropsychiatric disorders including substance use disorders (SUDs). This study focused on the synthesis and evaluation of a novel series of benzothiazole analogues designed to target D4R. We identified several compounds with high D4R binding affinity (Ki ≤ 6.9 nM) and >91-fold selectivity over other D2-like receptors (D2R, D3R) with diverse partial agonist and antagonist profiles. Novel analogue 16f is a potent low-efficacy D4R partial agonist, metabolically stable in rat and human liver microsomes, and has excellent brain penetration in rats (AUCbrain/plasma > 3). 16f (5–30 mg/kg, i.p.) dose-dependently decreased iv cocaine self-administration in rats, consistent with previous results produced by D4R-selective antagonists. Off-target antagonism of 5-HT2A or 5-HT2B may also contribute to these effects. Results with 16f support further efforts to target D4R in SUD treatment. |
| doi_str_mv | 10.1021/acs.jmedchem.3c00734 |
| format | Article |
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Benjamin ; Sibley, David R. ; Stewart, Kent D. ; Wu, Chun ; Hemby, Scott E. ; Keck, Thomas M.</creatorcontrib><description>Pharmacological targeting of the dopamine D4 receptor (D4R)expressed in brain regions that control cognition, attention, and decision-makingcould be useful for several neuropsychiatric disorders including substance use disorders (SUDs). This study focused on the synthesis and evaluation of a novel series of benzothiazole analogues designed to target D4R. We identified several compounds with high D4R binding affinity (Ki ≤ 6.9 nM) and >91-fold selectivity over other D2-like receptors (D2R, D3R) with diverse partial agonist and antagonist profiles. Novel analogue 16f is a potent low-efficacy D4R partial agonist, metabolically stable in rat and human liver microsomes, and has excellent brain penetration in rats (AUCbrain/plasma > 3). 16f (5–30 mg/kg, i.p.) dose-dependently decreased iv cocaine self-administration in rats, consistent with previous results produced by D4R-selective antagonists. Off-target antagonism of 5-HT2A or 5-HT2B may also contribute to these effects. Results with 16f support further efforts to target D4R in SUD treatment.</description><identifier>ISSN: 0022-2623</identifier><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.3c00734</identifier><identifier>PMID: 37646374</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Benzothiazoles - pharmacology ; Benzothiazoles - therapeutic use ; Brain ; Cocaine - pharmacology ; Humans ; Rats ; Serotonin ; Substance-Related Disorders</subject><ispartof>Journal of medicinal chemistry, 2023-09, Vol.66 (17), p.12141-12162</ispartof><rights>2023 The Authors. Published by American Chemical Society</rights><rights>2023 The Authors. 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Results with 16f support further efforts to target D4R in SUD treatment.</description><subject>Animals</subject><subject>Benzothiazoles - pharmacology</subject><subject>Benzothiazoles - therapeutic use</subject><subject>Brain</subject><subject>Cocaine - pharmacology</subject><subject>Humans</subject><subject>Rats</subject><subject>Serotonin</subject><subject>Substance-Related Disorders</subject><issn>0022-2623</issn><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kctOHDEQRS0UBBOSP4giL7PpSfnRr1VEJgQiIYUFbLKxPDVl2qi7PbG7I8HXY5gBJZusalH33nocxj4IWAqQ4rPFtLwbaIMdDUuFALXSB2whSgmFbkC_YQsAKQtZSXXM3qZ0BwBKSHXEjlVd6UrVesF-XXU2DhZDH27vuR03_LqjaLc0Tx75VZhonLzteXD8K40PYeq8fQg98dPRZstMibsQ-Sqg9SPxm0T8m08hbii-Y4fO9one7-sJu_l-dr26KC5_nv9YnV4WVpcwFQo3ijTJukKBJNCRq9dSNlihrgBbCXVTl6pWSE3ZOGv1WroWhETpNDVKnbAvu9ztvH76R9442t5sox9svDfBevNvZ_SduQ1_jIBSgGrbnPBpnxDD73zSZAafkPrejhTmZGQenGW6hSzVOynGkFIk9zpHgHniYjIX88LF7Llk28e_d3w1vYDIAtgJnu1hjvm96f-Zj9tHnx0</recordid><startdate>20230914</startdate><enddate>20230914</enddate><creator>Boateng, Comfort A.</creator><creator>Nilson, Ashley N.</creator><creator>Placide, Rebekah</creator><creator>Pham, Mimi L.</creator><creator>Jakobs, Franziska M.</creator><creator>Boldizsar, Noelia</creator><creator>McIntosh, Scot</creator><creator>Stallings, Leia S.</creator><creator>Korankyi, Ivana V.</creator><creator>Kelshikar, Shreya</creator><creator>Shah, Nisha</creator><creator>Panasis, Diandra</creator><creator>Muccilli, Abigail</creator><creator>Ladik, Maria</creator><creator>Maslonka, Brianna</creator><creator>McBride, Connor</creator><creator>Sanchez, Moises Ximello</creator><creator>Akca, Ebrar</creator><creator>Alkhatib, Mohammad</creator><creator>Saez, Julianna</creator><creator>Nguyen, Catherine</creator><creator>Kurtyan, Emily</creator><creator>DePierro, Jacquelyn</creator><creator>Crowthers, Raymond</creator><creator>Brunt, Dylan</creator><creator>Bonifazi, Alessandro</creator><creator>Newman, Amy Hauck</creator><creator>Rais, Rana</creator><creator>Slusher, Barbara S.</creator><creator>Free, R. 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| source | ACS Publications; MEDLINE |
| subjects | Animals Benzothiazoles - pharmacology Benzothiazoles - therapeutic use Brain Cocaine - pharmacology Humans Rats Serotonin Substance-Related Disorders |
| title | Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder |
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